Human genetic diversity through chromosome structure

The most detailed search yet for genetic differences between healthy humans …

A few years ago, people were focusing on the lack of human genetic diversity. At the level of individual DNA bases, any two humans were well over 99 percent identical. With the completion of the human genome, however, researchers have been able to detect differences in the structure of the chromosomes themselves, including deletions, extra material, and other changes. An early access publication in Science describes the most detailed search yet for these changes.

The study used a clever method of getting increased size resolution while allowing the detection of a greater variety of changes compared to prior work. The researchers fragmented human chromosomes in a way that all the fragments should be close to a single, average size (3kb, in this case). The ends of these fragments were sequenced, and the sequenced matched with the existing human genome. If the two matches weren't 3kb apart, the researchers knew that there was some sort of difference. Using this method allowed them to identify hundreds of chromosomal changes with an average difference of about 650 bases.

They performed the study using DNA from two individuals, and found that they had 761 and 887 structural variations (SVs) compared to the reference human genome. The subjects are of African and European origin, but half of these SVs were present in both of them, suggesting that some of them might be older than the human species itself. Most SVs were fairly small—a third were less than 5kb long—but about 17 percent appear likely to affect gene activity, as they eliminate coding regions and fuse or flip portions of a gene. Basic metabolic genes were rarely affected, with immune and olfactory proteins being the most commonly altered.

Overall, the researchers estimate that, combined, these structural differences change more DNA than all the single base changes combined. So, it turns out that the human population is probably over twice as diverse as originally expected, at least on the DNA level.